Production of 2,4-dihydroxyquinoline

ABSTRACT

Production of 2,4-dihydroxyquinoline starting from Nacetoacetylanthranilic acid esters.

United States Patent Sturm et al. 1451 Aug. 8, 1972 [541 PRODUCTION OF2,4-

DIHYDROXYQUINOLINE [56] References Cited [72] Inventors: Hans-JuergenSturm, Gruenstadt; UNITED STATES PATENTS Helmut Goerth L dwi haf bothGermany gs 3,025,299 3/1962 Pfister et al ..260/289 [73] Assignee:Badische Anilin & Soda-Fabrik Ak- FOREIGN PATENTS OR APPLICATIONStieljgesellschflft, Ludwigshafen/ 488,203 11/1952 Canada ..260/289 Rhme,Germany 40/18110 8/1965 Japan ..260/289 22 Filed; May 9 1969 1,509,4682/ 1968 France ..260/289 [21] Appl. No.2 825,956 Primary Examiner-DonaldG. Daus Att0rney--Johnston, Root, OKeeffe, Keil, Thompson 30 ForeignApplication Priority Data Shm'eff May 22, 1968 Germany ..P 17 70 480.2[57] ABSTRACT 52 U.S. c1 ..260/283 SY, 260/289 R, 260/471 R Stamng fmm[51] Int. Cl. ..C07d 33/38 [58] Field of Search ..260/289 R, 283 SY 3Claims, No Drawings PRODUCTION OF 2,4-DIHYDROXYQUINOLINE This inventionrelates to a process for the production of 2,4-hydroxyquinoline.

We have found that 2,4-dihydroxyquinoline can be prepared in a veryadvantageous way by converting a N-acetoacetylanthranilic acid esterhaving the general formula (I):

OOOR

where R denotes an alkyl radical having from one to four carbon atoms,by means of aqueous alkali or alkaline earth into the alkali metal oralkaline earth metal salt of 3-acetyl-2,4-dihydroxyquinoline or by meansof additional acidification into 3-acetyl-2,4-dihydroxyquinoline havingthe formula (II):

311 fie OCH: N H (II) and deacetylating this product to2,4-dihydroxyquinoline.

Examples of the radical R are methyl, ethyl, npropyl, isopropyl, n-butylor isobutyl, methyl and ethyl being preferred.

Compounds having the general formula (I) are acessible easily and inexcellent yields form the corresponding anthranilic esters by reactionwith diketene.

Examples of alkalies or alkaline earths are: sodium hydroxide, potassiumhydroxide, calcium hydroxide and barium hydroxide, sodium hydroxidebeing preferred.

Ring closure to form the compounds having the formula (I1) takes placein aqueous alkali which contains for example from 1 to 10 equivalents,preferably from 1.5 to 6 equivalents, of alkali metal hydroxide oralkaline earth metal hydroxide per mole of the compound having theformula (I). The alkali metal salt or alkaline earth metal salt of3-acetyl-2,4-dihydroxyquinoline is first formed in the reaction and thismay be converted into 3-acetyl-2,4-dihydroxyquinoline by acidification.

Deacetylation to 2,4-dihydroquinoline is carried out in a strong acid orin alkaline solution.

Examples of strong acids are hydrobromic acid, perchloric acid,phosphoric acid or preferably sulfuric acid. When sulfuric acid is used,for example 5 to times, preferably from 6 to 8 times the amount of 50percent to 96 percent, preferably from 70 percent to 90 percent, acid isadded.

Sodium hydroxide, potassium hydroxide or calcium hydroxide may be usedfor example for deacetylation in alkaline solution, the deacetylationtemperature being above 100 C, preferably above 140 C. When usingaqueous alkaline solutions it is therefore necessary to use pressureresistant vessels. The use of pressure vessels may be avoided however bywholly or partly replacing water by a solvent of higher boiling point,such as alcohols, glycols or glycol ethers. Examples are diethyleneglycol, triethylene glycol, methyl diglycol or ethyl diglycol.

A convenient method for the production of 2,4- dihydroxyquinolineconsists in introducing the N- acetoacetylanthranilic ester into waterat room or higher temperature (for example C) and then running incaustic alkali solution. The whole is stirred for half an hour to 2hours at from 70 to C.

When the deacetylation is to be carried out in alkaline solution, thereaction temperature is then raised to to 190 C, preferably from to C,and the reaction mixture is kept at this temperature for from 2 to 10,preferably 4 to 8, hours. For ring closure and deacetylation it isadvantageous to use from 2 to 10, preferably 4 to 6, equivalents ofalkali metal hydroxide or alkaline earth metal hydroxide per mole of thecompound having the formula (I), added all the once at the beginning ofthe reaction or preferably in several portions. The concentration of thealkaline solutions should preferably be from 1.5 to 5N.Deacetylation inalkaline solution makes it possible, starting from compounds having theformula (I), to carry out the production of 2,4-dihydroxyquinoline in asingle vessel, and the product can be isolated as the alkali metal oralkaline earth metal salt.

If deacetylation is to be carried out in strong acid, it is advantageousto precipitate the reaction product present after ring closure by addingacid and thus isolating it as 3-acetyl-2,4-dihydroxyquinoline. The 3-acetyl-2,4-dihydroxyquinoline is then added to sulfuric acid and theresulting suspension is heated. After about half an hour to 3 hoursheating at a temperature of from about 90 to 130 C, the reaction mixtureis allowed to flow into water and the precipitated reaction product2,4-dihydroxyquinoline is isolated and dried.

The acetyldihydroxyquinoline may be reacted dry or moist, any waterpresent being compensated for by adding appropriate amounts ofconcentrated acid so that the acid concentration in the suspensionamounts to from 70 to 90 percent after the mixing.

Cyclization of ethyl acetoacetylanthranilate to 3-acetyl-2,4-dihydroxyquinoline by heating in alcoholic caustic potashsolution (K. Ogura, H Sazaki, S. Seto, Bl. chem. Soc. Japan, 38, 306(1965)) and of the methyl ester by boiling with sodium in toluene or byheating for several hours with sodium methylate in methanol and ether(R. Lacey, J. Chem. Soc., London,

1954, 850) is known. It is very surprising that the ring closure canalso be achieved in dilute aqueous caustic alkali solution, and indeedunder conditions which are normally chosen for hydrolyzing esters.

As compared with conventional industrial method for the production of2,4-dihydroxyquinoline in which N-acetylanthranilic acid is cyclized inan anhydrous melt of sodium hydroxide and potassium hydroxide whichcontains a considerable amount of sodamide at temperatures of from 150to C (see BIOS 1153, 323), the new process offers great advantages. Inthe prior methods the melt has to be very carefully dehydrated prior tothe actual reaction and similarly the N-acetylanthranilic acid has to beabsolutely dry because sodamide reacts explosively with moisture.Moreover the melt has a strong corrosive effect. In contrast, the newprocess is more economical and less complicated, and it does not requireany special safety precautions whatever in carrying it out.

It is very surprising that in deacetylation in alkaline solution in theabsence of solubilizers, the reaction will only proceed when causticalkaline solutions are used which are not too concentrated; for examplecaustic alkali solutions having a content of more than 50 percent ofalkali are inactive.

The invention is illustrated by the following Examples. Parts andpercentages specified in the following Examples relate to weight.

EXANIPLE l 250 parts of ethyl-N-acetoacetylanthranilate is added to 1800parts of water at 80 C so that the ester melts. The whole is heated to90 C, 160 parts of 50 percent caustic potash solution is run in and thewhole is stirred for 1 hour at this temperature. Then it is cooled toabout 70 C, slightly acidified with dilute sulfuric acid, further cooledto about 40 C and the precipitate is suction filtered and washed untilneutral. 436 parts of moist 3-acetyl-2,4-dihydroxyquinoline is obtainedhaving a water content of 58 percent, i.e. a yield of 89.5 percent ofthe theory calculated as dry product.

The moist 3-acetyl-2,4-dihydroxyquinoline is introduced into 915 partsof concentrated sulfuric acid in such a way while stirring well that thetemperature does not rise above 100 C. After all has been added, themixture is heated to 125 C, stirred for 2 hours at this temperature andthen allowed to flow into 3,300 parts of water. The whole is allowed tocool, the precipitate is suction filtered, washed until neutral anddried. 138 parts of 96 percent 2,4-dihydroxyquinoline is obtained, i.e.a yield of 91 percent of the theory.

EXAMPLE 2 755 parts of methyl anthranilate and 450 parts of diketene arecaused to react at 120 C. The liquid reaction product is allowed to flowinto 9,500 parts of water, the mixture is heated to 90 to 100 C and 600parts of concentrated caustic soda solution is slowly added. The wholeis stirred for 2 hours at about 95 C, cooled to about 60 C and adjustedto pH 4 with concentrated sulfuric acid. The whole is then stirred forhalf an hour and the reaction product is suction filtered, washed untilneutral and dried. 888 parts of 3- acetyl-2,4-dihydroxyquinoline havinga melting point of from 245 to. 248 C is obtained, i. c. 87.7 percent ofI EXAMPLE 3 470 parts of methyl acetoacetylanthranilate and 800 parts of50 percent caustic soda solution are added to 3,500 parts of water atabout 80 C in a stirred pressure vessel. The whole is stirred for halfan hour at 90 to 100 C, then heated to 160 C, stirred for 6 hours atthis temperature, cooled, the reaction mixture diluted somewhat withwater and acidified. The precipitate is suction filtered, washed untilneutral and dried. 290 parts of 96 percent 2,4-dihydroxyquinoline isobtained.

EXANIPLE 4 The procedure of Example 3 is followed but only 3,000 partsof water is used. After the reaction is over the product is not dilutedand acidified but the sodium salt of dihydroxyquinoline is allowed tocrystallize out completely. 500 parts of moist filter cake is obtainedhaving a content of 58 percent of the sodium salt of dihydroxyquinoline,equivalent to 289 parts of 100 percent the sodium salt of2,4-dihydroxyquinoline.

EXAMPLE 5 400 parts of ethyl anthranilate is caused to react at from 110to 130 C with 210 parts of diketene. The reaction product is run as aliquid into an autoclave filled with 4,750 parts of water. The whole isheated at to 90 C and 660 parts of about 50 percent caustic potashsolution is added. The whole is stirred for 1 hour at 90 C, then heatedslowly to 170 C, stirred for another 5 hours at this temperature,cooled, diluted with a little water and acidified. The precipitate issuction filtered, washed until neutral and dried. 343 parts of 94percent 2,4-dihydroxyquinoline is thus obtained.

EXAMPLE 6 377 parts of methyl anthranilate is allowed to react with 255parts of diketene at about 120 C. The liquid reaction product is run offwhile hot into an autocalve containing a suspension of 600 parts ofquicklime in 4,700 parts of water at 80 C. After stirring for 1 hour at90 C, the whole is heated to 180 C, stirred for 8 hours at thistemperature, cooled to room temperature and the precipitate is suctionfiltered. The moist filter cake is stirred into hot 5 percent causticsoda solution and the mixture is filtered. The filtrate is acidified.After suction filtration, washing and drying, 244 parts of 89 percent2,4-dihydroxyquinoline' is obtained.

EXAMPLE 7 A mixture of 117 parts of methyl acetoacetylanthranilate and420 parts of methyl diglycol is heated to C in a stirred flask having asuperimposed distillation bridge. 200 parts of about 50 percent causticsoda solution is then run in slowly at such a rate that the internaltemperature does not exceed 95 C. The whole is stirred for minutes at Cand the temperature is then slowly raised to 175 C so that a mixture ofmethanol, water and some methyl diglycol distils off. The contents ofthe flask are stirred for 4 hours at 175 C, then cooled to about C andaboutv 300 parts of water is added. The whole is made clearly acid withhydrochloric acid, cooled to room temperature, suction filtered, washeduntil neutral and dried. 68 parts of 92 percent 2,4-dihydroxyquinolineis obtained.

We claim:

l. A process for the production of 2,4-dihydroxyquinoline whichcomprises forming the alkali or alkaline earth metal salt of3-acetyl-2,4-dihydroxyquinoline by reacting a compound of the formula-COOR wherein R is alkyl of one to four carbon atoms, with from 1 toequivalents of alkali or alkaline earth metal hydroxide in aqueoussolution at a temperature of about 70 C. to 100 C., acidifying saidalkali or alkaline earth metal salt into 3-acetyl-2,4-dihydroxyquinolineand then deacetylating said 3-acetyl-2,4-

2. A process as claimed in claim 1 wherein said hydroxide is sodiumhydroxide.
 3. A process as claimed in claim 1 wherein said concentratedacid used for deacetylating said 3-acetyl-2,4-dihydroxyquinoline issulfuric acid.